A groundbreaking set of recent studies revealed that homozygous "mutator" mice expressing a proofreading deficient mitochondrial polymerase gamma (Polg ) accumulate both mtDNA point mutations and large deletions in association with a premature aging phenotype, demonstrating that somatic mitochondrial DNA (mtDNA) mutations can contribute to an aging phenotype. Large mtDNA deletions rather than point mutations have been proposed to be the driving force behind the aging phenotype, in part based on the lack of an overt phenotype in heterozygous mutator mice despite high levels of mtDNA point mutations and normal levels of deletions. However, we strongly argue in favor of the alternative hypothesis that mtDNA point mutations drive the aging phenotype in the mutator mice, an argument supported by our preliminary data, and propose to further test this hypothesis with particular attention to the neurological phenotype in the heterozygous mice. Several studies have demonstrated a normal age-related loss of dopaminergic substantia nigra (SN) neurons, as well as a marked enhancement with aging in the vulnerability of these neurons to mitochondrial toxins. However, studies of these or other age-related changes in the brain are lacking in the Polg mutator mice. Elucidating the cause of age-related vulnerabilities in the brain represents a critical step in advancing our understanding of normal aging in the brain and potentially of age-related neurodegenerative diseases such as Parkinson's disease (PD). We hypothesize that somatic mtDNA point mutations are a major cause of these age-related vulnerabilities of dopaminergic neurons, and therefore we predict that both heterozygous and homozygous Polg mutator mice will show increased spontaneous age related loss of dopaminergic neurons in addition to an enhanced susceptibility to toxin-induced degeneration of dopaminergic SN neurons compared to wild-type littermate controls. The proposed studies will directly test these predictions, and thus will help to clarify the important issue of the role of mtDNA point mutations in the aging brain. PUBLIC HEALTH RELEVANCE: set of cells in the brain that produce dopamine degenerate in Parkinson's disease. These same cells show a greatly enhanced vulnerability with advancing age to death from exposure to certain toxins, potentially accounting for the dramatic rise with age in the incidence of Parkinson's disease. We propose a series of studies to investigate the hypothesis that acquired mitochondrial DNA mutations account for the age-related vulnerability of these brain cells to degeneration.